Asymmetric Catalytic Aldol Reaction of activated ketonesters withα-isothiocyanato imide
Zhen QiaoDepartment of ChemistryDrexel University, Philadelphia, PA 19104Submitted December 8, 2012
Abstract: Bispidines, the structural core of alkaloids, had opened up the opportunity to develop new catalyst by introduction of appropriate chiral group. We designed and synthesized a kind of novel organocatalysts by introducing facile amino acids into the bicyclic bispidine framework for the asymmetric reaction.
Asymmetric catalytic Aldol Reaction is promising universally. Drug-lead synthesis by rapid construction of chiral molecular complex regarding to thebiologically relevant framework using a highly efficient method is a key goal of organic synthesis because of the important bioactivities exhibited by the moleculesbearing a spirooxindole-type framework.Herein, we present a quite highly efficientand convenient strategy that provides rapid construction of unique optically activespirooxindole synthesized by N, N’-dioxide metal complex through asymmetric Aldol reaction. In this dissertation, chiral N, N’-dioxide Fe (II) complex and Ca (II) was applied successfully in the asymmetric Aldol reaction of activated ketonesters and isothiocyanates. After optimization of the reaction conditions, the product can potentially be obtained with high yield and enantioselectivity. This work provides new catalytic system for the Aldol reactions. Key words: Asymmetric catalysis; Aldol reaction; isothiocyanate; activated ketonesters; N, N’-Dioxide Fe (II) and Ca (II) complex;
1.1Introduction
Aldol condensations are a reaction that combines two carbonyl compounds (the original experiments used aldehydes) to form a new β-hydroxy carbonyl compound. Different kinds ofnucleophiles can be used in this reaction, including enolates, enolate anions, ketones and aldehydes. Aldol reactions are widely used for daily chemicals such as Pentaerythritol[1] and Atorvastatin’s synthesis.[2][3][4]
Catalytic chiral Aldol condensations are famous due to low quantities of catalyst required and are widely usage in asymmetric reactions. Catalytic asymmetric aldol reaction can be used for chiral β-hydroxy carbonyl compound. Nowadays, there have been developed a lot of chiral catalyst, including organocatalysis and transition metal complex. Among the well-established catalytic system, reaction of aldehyde as electrophiles has been most developed in syntheses. However, because of low electrophilicity and larger hindrance, the ketone functional group has proven to be difficult in participation in Aldol reaction.
The work of this kind of asymmetric reaction is focused on the modification of nucliphiles. α-isothiocyanato imide can act as C-nucleophiles in addition reaction, by forming chiral oxazolidin-2-thione.
There are several ways to control the stereochemistry of Aldol reaction: (1) Reagents controlled reaction
The substrate of this kind of reaction is generally achiral aldehyde, reacting with chiral adjuvants, such as ester, amide, imide to form chiral enolates. (2) Substrate controlled -
The chiral substrate is generally an aldehyde with the chiral center in α-position. And the nucleophiles are generally achiral enolates. In this method, we can judge the enantioselectivity by Cram-Felkin-Ahn rule. (3) Double asymmetric synthesis -
In this method, both the substrate and reagents are chiral. Only when the aldehyde and attacking reagents have the same chirality results in high enantioselectivity. Otherwise, significant reduction in enantioselectivity is observed. (4) Asymmetric Aldol reaction controlled by chiral catalyst -
The reaction of chiral catalyst with achiral substrate is widely known. Since the Mukaiyama group found the addition reaction of Lewis acid intermediate silyl enolate esters with analdehyde, many novel catalysts have been used for the Aldol reaction. Classical silyl enolate esters (from esters, lipid and ketone) do not react with aldehyde under room temperature. However, when adding Lewis acids such as TiCl4, SnCl4, AlCl3, BCl3, BF3·Et2 and ZnCl2, the result is an acceleration of the addition reaction of silyl enol esters and aldehyde to obtain β-OH compounds. In recent years, it has been reported that the proline derivative can facilitate in catalyzing Aldol reaction. The most predominant of this kind of catalyst is a non-modified ketone that can act as a donor of the reaction.
Figure1-1
Figure1-1 is the classical Aldol reaction. Based on this mechanism, there are two reaction processes: one is non-substitute ester enolate 5 reacted with aldehyde, which is a process that produces a mono chiral center secondary alcohol compound 6; the second process is either a mono-substitute or double-substitute derivative enolate 7, 8 and 9, this process can form two new chiral centers, and this process is the future of the Aldol reaction’s development.
Figure1-2
Figure 1-3
By further research and computational chemistry, people brought up the possibility of a transition state in the Mukaiyama reaction. (Figure 1-3)[5]
Aldol reaction can be categorized by different donors: (1) enolate as the donors
The aldehyde, ketone, ester or amines with acidic α-proton, can be de-protonated under basic conditions and can be turned into a highly active enolate. The enolate reacts with a ketone or aldehyde forming product of Aldol Reaction. (2) Aldol reaction by forming silyl enolate
Also known as the Mukaiyama reaction, it is performed generally under the presence of a Lewis acid to catalyze the aldehyde with ketone or ketone derivatives like silyl-ethers to form β-hydroxyl carbonyl compound. This particular reaction usually requires acidic or mild acidic conditions due to the presence of silyl-ethers, which also reduces the stability of the reaction. (3) Direct Aldol reaction -
The two categories above are examples of aldol reaction that require the modification of the donor by a silyl enolate. Direct Aldol reaction is the reaction without modification of the aldehyde or ketone. It is categorized as a green chemistry reaction and is easier to handle, which has gained growing acceptance. In this kind of reaction, ketones usually undergo an enamine or imine transition state to participate in the reaction. The catalyst can be organometallic reagents or non-metal amphoteric catalyst, such as a Bronsted base-Lewis acid, Bronsted base-Bronsted acid, Lewis base-Lewis acid. 1.2 History of asymmetric Aldol reaction
Playing a key role in the organic synthesis, Aldol reactions attract more and more researchers in the organic chemistry field. However, the application of the Aldol reaction is limited due to the multi-products produced in the reaction. In the year 1974, Mukaiyama firstutilized the Lewis acid TiCl4 to catalyze the addition reaction of silyl enolates with an aldehyde under mild conditions and obtained very promising results. [6] For asymmetric ketones, the reaction can produce products by attacking from one specific side. Due to the significance of the result, the reaction is named by its founder: the Mukaiyama Aldol Reaction. This laid the foundation for his future research.
Figure1-4
Tin, boron, gold, copper, titanium, silver etc. can act as Lewis acid to catalyze the Mukaiyama Aldol reaction. The most successful is the Ti (IV) BINOL complex to catalyze the Mukaiyama Aldol reaction. (Figure 1-5)[7].
Figure 1-5
In the year 1997, Shibasaki developed the complex of BINOL and LaCl3 (binaphtholate LLB) [8].
This kind of catalyst shares the property of a Lewis acid (La atom) and a Bronsted base (KOH). It has the capacity to activate the substrate and nucleophiles at the same time. It is one of the ideal catalysts for Direct Aldol reactions. The key step is the de-protonation of the ketone (I to II). At the same time, the catalyst reacts with aldehyde to form the activated aldehyde (II to III), then comes to the full aldol reaction (III to IV) (Figure 1-6).
Figure 1-6
Except for Shibasaki’s bi-function metal Lewis acid/Bronsted base system, Trost and Shibasaki developed another mono-metal Lewis acid/Bronsted base catalyst system. (Figure 1-7)[9] The mechanism is similar to the bi-functional system, but only difference is in this system, and there is only one kind of metal (rephase this sentence).
Figure1-7
Although Lewis acid and Bronsted base can catalyze direct Aldol reaction, this reaction must be carried out under anhydrous and anaerobic circumstances, and some of the metal involved is not considered in the realm of green chemistry. As a result, the application of this kind of catalyst is limited.
In 2000, List and Barbas in Scripps Institute first found that proline catalyzed direct Aldol reaction of acetone and aldehyde. (Figure 1-8)[10].
Figure 1-8
List and Barbas had given a probable mechanism: the amine group of proline attacks the carbonyl group of acetone, forming the imine by dehydration, followed by formation of the strong enolate by de-protonated the α-proton; the donor of the Aldol reaction is activated, through a six-member ring, and the reaction is completed. The configuration of proline determines the configuration of the product. (Figure 1-9). The conditions are mild, and can be done in ambient atmosphere. Standing out as organic small molecule, proline can yield a more beneficial future for the direct Aldol reaction. Many more systems catalyzed by organic small molecules are currently being investigated and developed.
Figure 1-9
1.3 Proline and other organic small molecules catalyzed Aldol reaction
List group [11] took proline as an example and did research on other ketones (cyclohexanone, cyclopentanone) on Aldol reaction, and got 22-77% yield and as high as 95% enantioselectivity. By comparison of the energy diagram and X-ray analysis, they found the reason for the well-controlled stereochemistry of the reaction and they used the following method to synthesis (S)-Ipsenol. (Figure 1-10).
Figure 1-10
Later on Maruoka group [11] and Zhao group [12] reported activated ketone acting as acceptor of the asymmetric Aldol reaction, respectively. And Maruoka group successfully used this method for the synthesis of (S)-2-cyclohexyl-2-phenyl hydroxyethanoic acid. (Figure 1-11)
Figure 1-11
Figure 1-12
In 2006, Kotsuki group [13] reported the synthesis of Culex mosquito ovipositon pheromones by proline catalyzed the direct Aldol reaction. (Figure 1-12) Except for the direct aldol reaction, many different varieties of aldol reactions were developed later on. Differ from normal Aldol reaction using ketone as the acceptor; cross Aldol condensations involve the reaction of an aldehyde with an aldehyde.Jørgensen group [14] reported the first asymmetric cross Aldol reaction and achieved high yield and enantioselectivity. However, the amount of the catalyst can be as high as 50 mol percent.
Cross Aldol reaction met this significant challenge because of two huge problems. First, it is more difficult for the activity of the enolate formed by aldehyde with the catalyst than ketone with the catalyst; second, the product of the Aldol reaction can continue to react in another Aldol reaction, which can result in unwanted by-products in the reaction system. Further research has been done since to alleviate such issues. [15] People overcame this problem by modifying the aldehyde of greater α-hindrance or adding excess aldehyde to the reaction system.（Figure 1-13）
Figure 1-13
Many more organic small molecules of proline derivatives [16] were developed to catalyze Aldol reaction. (Figure 1-14). For example, chiral diamine, amide, azole, cinchonine derivatives, piperidine derivatives etc. can activate the substrate by hydrogen bonding.
Asymmetric Aldol reactions have undergone the existence of silyl enolate catalyst to Lewis acid metal catalyzed direct Aldol reaction. Since McMillan, List and Barbas developed asymmetric Aldol reaction catalyzed by proline, many organic small molecules are developed and successfully used for this reaction. In addition, the reaction mechanism became better understood as the research carried on. The expansion of the substrate became popular among the chemists, which can be used for synthesizing natural products and bio-active molecules.
1.4Direct asymmetric Aldol Reaction of α-isocyanate and isothiocyanate (imide) as donor
People developed a reaction using isocyanate and isothiocyanate (imide) as donor during the time of development Aldol Reaction. α-isocyanate is an important precursor in the synthesis of α-amino acid enol compound. The above reaction can take place only in the weakly alkaline such as tertiary amines or potassium carbonate. α-amino acid enolate with an electrophilic reagent can be obtained different α-amino acid derivatives easily. As early as 1985 [17], it was reported that the CuCl-Et3N system can catalyze Aldol Reaction of isocyanate. The authors used the product in the synthesis of β-hydroxy-α-amino acid successfully. They believed the Lewis acid CuCl activated the α-carbon of the isocyanate. However, triethylamine captured the enolate of α-hydrogen-forming isocyanate, which was actived with the aldehyde to obtain the Aldol product. Therefore, the authors believe that the the formation of the isocyanate enolate intermediate was the critical step in the reaction dimensional control.
The first example of catalytic asymmetric Aldol reaction of the isocyanate was reported by Ito and Hayashi [18]. They used the complex of phosphorus and metallic gold to catalyze reaction. The experiments showed that the non-enantioselectivity and enantioselectivity had a great relationship with the structure of the amino acid chain in the ligand.
Figure 1-14 Table 1.1 Gold (I)-catalyzed asymmetric aldol reaction (R = Me)
This catalyst can get very good results to aryl substituted aldehyde and unsaturated aldehydes. However, it had a very low enantioselectivity of heterocyclic-substituted aldehyde. This method is applied to the total synthesis of amino acids MeBmt [19] successfully. It was found that metallic gold was becoming a complex with isocyanate ester during the reaction by IR analysis of transition state. But metallic silver may be complexing with one molecule or two molecules, which is a balance in the middle. To form the excessive state of the phosphorus ligand with the metal complex or isocyanate was the key to high selectivity. Thus, they proposed a possible transition states (Figure 1-15).
Figure 1-15
Subsequently, it was reported the Aldol reaction of α-methyl-substituted ethyl isocyanate with aldehyde [20] by this type of catalyst, and the direct Aldol reaction of isocyanate phospholipids [21] and isocyanurate tosylate [22] with aldehyde. (Figure 1-16)
Figure 1-16
In addition to the metal gold that had been used in catalytic the Aldol Reaction of isocyanate , rhodium [23] has also been used in catalytic asymmetric Aldol Reaction of α-cyanate successfully to obtain 93% ee in the products. (Figure 1-17)
Figure 1-17
In the development of Aldol donor, in addition to the isocyanate and the diisocyanate, the Aldol product of the isothiocyanate (imide) also can obtain the amino acid derivatives through a simple derivation. Willis Group [24] first reported the preparation of Aldol reaction racemic with aldehyde and isothiocyanate in 2005. They use magnesium with triethylamine as a catalyst, with a pyridine as additives, which had a high overall yield on most substrate chemicals. The trade-off was the significant reduction in diastereoselectivity. In the experiments, they found that the type of metal and a counter ion had a great influence on the reaction yield. (Figure 1-18)
Figure 1-18
Subsequently, their group achieved the asymmetry at first [25]. In the elicitation of preparation of the racemic, they attempted to achieve a lone asymmetric product by the introduction of the chiral catalyst, using the complex of magnesium and oxazoline to catalyze the reaction. ( Figure 1-19)
Figure 1-19
The structure of the ethyl ester can’t obtain enantioselectivity in the screening of isothiocyanate ester. It is required to introduce Evans adjuvants and use isothiocyanato imide 81 to facilitate the reaction to achieve better results. (Figure 1-20)
Figure 1-20
Table 1.2 The enantioselective addition of imide 81 to aromatic aldehydes.
a General conditions: imide 81 (1 equiv), aldehyde (1.1 equiv), Mg(ClO4)2 (10 mol%), 83 (11 mol%), i-Pr2EtN (20 mol%), CH2Cl2, -78 oC. b Isolated yields of combined diastereomers. c Measured by 1H-NMR spectroscopy. d ee value of major diastereomer, measured by chiral HPLC using Chiracel OD column.
It can be seen from the table that the catalytic reaction system is a bit complex. The reaction conditions demand -78 oC to get high selectivity. There is a limitation of the universality of the substrate, which only fit aliphatic substrates that the enantioselectivity proportion of trans: cis is 1:1 for the ortho position.
The Seidel group [26] catalyzed asymmetric isothiocyanato imide with aldehydes Aldol Reaction using small molecule of thiourea in 2008. Large number of aliphatic aldehydes can be catalyzed to non-enantioselective and enantioselective in a low amount of catalyst and a mild reaction condition. The non-enantioselective had a great breakthrough compared to the first cases reported which the results were moderate to good. The author showed the prospects for industrial applications by expanding the amount of the reaction substrate reaction. (Figure 1-21) Figure 1-21
For Aldol Reaction of the isocyanurate or isothiocyanate (imide), the current development of the receptor is an aldehyde, and there is almost no report of ketone. There were mainly two parts of challenges: 1) the activity of simple acetophenone was lower compared with the aldehyde; 2) the simple ketone had a relatively large steric hindrance, and the donor could not easily attack the substrate. (Figure 1-22)
Figure 1-22
Recently, Shibasaki group [27] has achieved a direct Aldol reaction with acetophenone and isothiocyanates for the first time. They make use of the complex of Schiffer alkali and magnesium to catalyze the reaction (Figure 1-20). The universality of the substrate is very wide, both the non-enantioselective and enantioselective can obtain good results, and the isothiocyanato can still have a good yield without adjuvants. This method was applied to the synthesis of optically active β-hydroxy-α-amino (Figure 1-23).
Figure 1-23
1.5 Conclusion
From the above literature, we found that the development of Aldol Reaction was step by step from first discovered Lewis acid which can promote the reaction to the development of a series to the central metal as a Lewis acid. Since the List and Barbas found to use proline to catalyze Aldol reaction, proline derivative, proline analogues catalyst and series of small organic molecules of diamines have been applied to the reaction successfully. The reaction conditions are more and more moderate. It was required a strict anhydrous anaerobic operation and -78 oC reactions to obtain a high enantioselectivity at first. Now many Aldol reactions were being in the aqueous phase directly and energy saving green. From the perspective of the development of the donor, it developed some value functional groups gradually. It need to pre-prepared silyl enol ether to a series of simple ketone ketone ester functional groups at first. The recently reported said the reactions with isocyanate or isothiocyanate ester (imide) can get many of the β-hydroxy-α-amino acid precursors.
The β-hydroxy-α-amino acid units have many important biologically active molecule skeletons. Aryl-substituted β-hydroxy-α-amino acid units are the main structural units of the many drug molecules. The natural product, such as vancomycin, ristocetin, diphenol amphotericin A having biological activity, and anti-inflammatory ring Marin et al. contains such structural unit. Currently, there are many ways to synthesize this structural unit. However, the Aldol reaction isothiocyanate ester (imide) with an aldehyde or ketone is the most direct and effective method for the synthesis of this molecule. It is possible to build the C-C bond step and generates two perspective chiral centers by this method.
Zhen QiaoDepartment of ChemistryDrexel University, Philadelphia, PA 19104Submitted December 8, 2012
Abstract: Bispidines, the structural core of alkaloids, had opened up the opportunity to develop new catalyst by introduction of appropriate chiral group. We designed and synthesized a kind of novel organocatalysts by introducing facile amino acids into the bicyclic bispidine framework for the asymmetric reaction.
Asymmetric catalytic Aldol Reaction is promising universally. Drug-lead synthesis by rapid construction of chiral molecular complex regarding to thebiologically relevant framework using a highly efficient method is a key goal of organic synthesis because of the important bioactivities exhibited by the moleculesbearing a spirooxindole-type framework.Herein, we present a quite highly efficientand convenient strategy that provides rapid construction of unique optically activespirooxindole synthesized by N, N’-dioxide metal complex through asymmetric Aldol reaction. In this dissertation, chiral N, N’-dioxide Fe (II) complex and Ca (II) was applied successfully in the asymmetric Aldol reaction of activated ketonesters and isothiocyanates. After optimization of the reaction conditions, the product can potentially be obtained with high yield and enantioselectivity. This work provides new catalytic system for the Aldol reactions.
Key words: Asymmetric catalysis; Aldol reaction; isothiocyanate; activated ketonesters; N, N’-Dioxide Fe (II) and Ca (II) complex;
1.1 Introduction
Aldol condensations are a reaction that combines two carbonyl compounds (the original experiments used aldehydes) to form a new β-hydroxy carbonyl compound. Different kinds ofnucleophiles can be used in this reaction, including enolates, enolate anions, ketones and aldehydes. Aldol reactions are widely used for daily chemicals such as Pentaerythritol[1] and Atorvastatin’s synthesis.[2][3][4]
Catalytic chiral Aldol condensations are famous due to low quantities of catalyst required and are widely usage in asymmetric reactions. Catalytic asymmetric aldol reaction can be used for chiral β-hydroxy carbonyl compound. Nowadays, there have been developed a lot of chiral catalyst, including organocatalysis and transition metal complex. Among the well-established catalytic system, reaction of aldehyde as electrophiles has been most developed in syntheses. However, because of low electrophilicity and larger hindrance, the ketone functional group has proven to be difficult in participation in Aldol reaction.
The work of this kind of asymmetric reaction is focused on the modification of nucliphiles. α-isothiocyanato imide can act as C-nucleophiles in addition reaction, by forming chiral oxazolidin-2-thione.
There are several ways to control the stereochemistry of Aldol reaction:
(1) Reagents controlled reaction
The substrate of this kind of reaction is generally achiral aldehyde, reacting with chiral adjuvants, such as ester, amide, imide to form chiral enolates.
(2) Substrate controlled -
The chiral substrate is generally an aldehyde with the chiral center in α-position. And the nucleophiles are generally achiral enolates. In this method, we can judge the enantioselectivity by Cram-Felkin-Ahn rule.
(3) Double asymmetric synthesis -
In this method, both the substrate and reagents are chiral. Only when the aldehyde and attacking reagents have the same chirality results in high enantioselectivity. Otherwise, significant reduction in enantioselectivity is observed.
(4) Asymmetric Aldol reaction controlled by chiral catalyst -
The reaction of chiral catalyst with achiral substrate is widely known. Since the Mukaiyama group found the addition reaction of Lewis acid intermediate silyl enolate esters with analdehyde, many novel catalysts have been used for the Aldol reaction. Classical silyl enolate esters (from esters, lipid and ketone) do not react with aldehyde under room temperature. However, when adding Lewis acids such as TiCl4, SnCl4, AlCl3, BCl3, BF3·Et2 and ZnCl2, the result is an acceleration of the addition reaction of silyl enol esters and aldehyde to obtain β-OH compounds. In recent years, it has been reported that the proline derivative can facilitate in catalyzing Aldol reaction. The most predominant of this kind of catalyst is a non-modified ketone that can act as a donor of the reaction.
Figure1-1
Figure1-1 is the classical Aldol reaction. Based on this mechanism, there are two reaction processes: one is non-substitute ester enolate 5 reacted with aldehyde, which is a process that produces a mono chiral center secondary alcohol compound 6; the second process is either a mono-substitute or double-substitute derivative enolate 7, 8 and 9, this process can form two new chiral centers, and this process is the future of the Aldol reaction’s development.
Figure1-2
Figure 1-3
By further research and computational chemistry, people brought up the possibility of a transition state in the Mukaiyama reaction. (Figure 1-3)[5]
Aldol reaction can be categorized by different donors:
(1) enolate as the donors
The aldehyde, ketone, ester or amines with acidic α-proton, can be de-protonated under basic conditions and can be turned into a highly active enolate. The enolate reacts with a ketone or aldehyde forming product of Aldol Reaction.
(2) Aldol reaction by forming silyl enolate
Also known as the Mukaiyama reaction, it is performed generally under the presence of a Lewis acid to catalyze the aldehyde with ketone or ketone derivatives like silyl-ethers to form β-hydroxyl carbonyl compound. This particular reaction usually requires acidic or mild acidic conditions due to the presence of silyl-ethers, which also reduces the stability of the reaction.
(3) Direct Aldol reaction -
The two categories above are examples of aldol reaction that require the modification of the donor by a silyl enolate. Direct Aldol reaction is the reaction without modification of the aldehyde or ketone. It is categorized as a green chemistry reaction and is easier to handle, which has gained growing acceptance. In this kind of reaction, ketones usually undergo an enamine or imine transition state to participate in the reaction. The catalyst can be organometallic reagents or non-metal amphoteric catalyst, such as a Bronsted base-Lewis acid, Bronsted base-Bronsted acid, Lewis base-Lewis acid.
1.2 History of asymmetric Aldol reaction
Playing a key role in the organic synthesis, Aldol reactions attract more and more researchers in the organic chemistry field. However, the application of the Aldol reaction is limited due to the multi-products produced in the reaction. In the year 1974, Mukaiyama firstutilized the Lewis acid TiCl4 to catalyze the addition reaction of silyl enolates with an aldehyde under mild conditions and obtained very promising results. [6] For asymmetric ketones, the reaction can produce products by attacking from one specific side. Due to the significance of the result, the reaction is named by its founder: the Mukaiyama Aldol Reaction. This laid the foundation for his future research.
Figure1-4
Tin, boron, gold, copper, titanium, silver etc. can act as Lewis acid to catalyze the Mukaiyama Aldol reaction. The most successful is the Ti (IV) BINOL complex to catalyze the Mukaiyama Aldol reaction. (Figure 1-5)[7].
Figure 1-5
In the year 1997, Shibasaki developed the complex of BINOL and LaCl3 (binaphtholate LLB) [8].
This kind of catalyst shares the property of a Lewis acid (La atom) and a Bronsted base (KOH). It has the capacity to activate the substrate and nucleophiles at the same time. It is one of the ideal catalysts for Direct Aldol reactions. The key step is the de-protonation of the ketone (I to II). At the same time, the catalyst reacts with aldehyde to form the activated aldehyde (II to III), then comes to the full aldol reaction (III to IV) (Figure 1-6).
Figure 1-6
Except for Shibasaki’s bi-function metal Lewis acid/Bronsted base system, Trost and Shibasaki developed another mono-metal Lewis acid/Bronsted base catalyst system. (Figure 1-7)[9] The mechanism is similar to the bi-functional system, but only difference is in this system, and there is only one kind of metal (rephase this sentence).
Figure1-7
Although Lewis acid and Bronsted base can catalyze direct Aldol reaction, this reaction must be carried out under anhydrous and anaerobic circumstances, and some of the metal involved is not considered in the realm of green chemistry. As a result, the application of this kind of catalyst is limited.
In 2000, List and Barbas in Scripps Institute first found that proline catalyzed direct Aldol reaction of acetone and aldehyde. (Figure 1-8)[10].
Figure 1-8
List and Barbas had given a probable mechanism: the amine group of proline attacks the carbonyl group of acetone, forming the imine by dehydration, followed by formation of the strong enolate by de-protonated the α-proton; the donor of the Aldol reaction is activated, through a six-member ring, and the reaction is completed. The configuration of proline determines the configuration of the product. (Figure 1-9). The conditions are mild, and can be done in ambient atmosphere. Standing out as organic small molecule, proline can yield a more beneficial future for the direct Aldol reaction. Many more systems catalyzed by organic small molecules are currently being investigated and developed.
Figure 1-9
1.3 Proline and other organic small molecules catalyzed Aldol reaction
List group [11] took proline as an example and did research on other ketones (cyclohexanone, cyclopentanone) on Aldol reaction, and got 22-77% yield and as high as 95% enantioselectivity. By comparison of the energy diagram and X-ray analysis, they found the reason for the well-controlled stereochemistry of the reaction and they used the following method to synthesis (S)-Ipsenol. (Figure 1-10).
Figure 1-10
Later on Maruoka group [11] and Zhao group [12] reported activated ketone acting as acceptor of the asymmetric Aldol reaction, respectively. And Maruoka group successfully used this method for the synthesis of (S)-2-cyclohexyl-2-phenyl hydroxyethanoic acid. (Figure 1-11)
Figure 1-11
Figure 1-12
In 2006, Kotsuki group [13] reported the synthesis of Culex mosquito ovipositon pheromones by proline catalyzed the direct Aldol reaction. (Figure 1-12) Except for the direct aldol reaction, many different varieties of aldol reactions were developed later on. Differ from normal Aldol reaction using ketone as the acceptor; cross Aldol condensations involve the reaction of an aldehyde with an aldehyde.Jørgensen group [14] reported the first asymmetric cross Aldol reaction and achieved high yield and enantioselectivity. However, the amount of the catalyst can be as high as 50 mol percent.
Cross Aldol reaction met this significant challenge because of two huge problems. First, it is more difficult for the activity of the enolate formed by aldehyde with the catalyst than ketone with the catalyst; second, the product of the Aldol reaction can continue to react in another Aldol reaction, which can result in unwanted by-products in the reaction system. Further research has been done since to alleviate such issues. [15] People overcame this problem by modifying the aldehyde of greater α-hindrance or adding excess aldehyde to the reaction system.（Figure 1-13）
Figure 1-13
Many more organic small molecules of proline derivatives [16] were developed to catalyze Aldol reaction. (Figure 1-14). For example, chiral diamine, amide, azole, cinchonine derivatives, piperidine derivatives etc. can activate the substrate by hydrogen bonding.
Asymmetric Aldol reactions have undergone the existence of silyl enolate catalyst to Lewis acid metal catalyzed direct Aldol reaction. Since McMillan, List and Barbas developed asymmetric Aldol reaction catalyzed by proline, many organic small molecules are developed and successfully used for this reaction. In addition, the reaction mechanism became better understood as the research carried on. The expansion of the substrate became popular among the chemists, which can be used for synthesizing natural products and bio-active molecules.
1.4 Direct asymmetric Aldol Reaction of α-isocyanate and isothiocyanate (imide) as donor
People developed a reaction using isocyanate and isothiocyanate (imide) as donor during the time of development Aldol Reaction. α-isocyanate is an important precursor in the synthesis of α-amino acid enol compound. The above reaction can take place only in the weakly alkaline such as tertiary amines or potassium carbonate. α-amino acid enolate with an electrophilic reagent can be obtained different α-amino acid derivatives easily. As early as 1985 [17], it was reported that the CuCl-Et3N system can catalyze Aldol Reaction of isocyanate. The authors used the product in the synthesis of β-hydroxy-α-amino acid successfully. They believed the Lewis acid CuCl activated the α-carbon of the isocyanate. However, triethylamine captured the enolate of α-hydrogen-forming isocyanate, which was actived with the aldehyde to obtain the Aldol product. Therefore, the authors believe that the the formation of the isocyanate enolate intermediate was the critical step in the reaction dimensional control.
The first example of catalytic asymmetric Aldol reaction of the isocyanate was reported by Ito and Hayashi [18]. They used the complex of phosphorus and metallic gold to catalyze reaction. The experiments showed that the non-enantioselectivity and enantioselectivity had a great relationship with the structure of the amino acid chain in the ligand.
Figure 1-14
Table 1.1 Gold (I)-catalyzed asymmetric aldol reaction (R = Me)
This catalyst can get very good results to aryl substituted aldehyde and unsaturated aldehydes. However, it had a very low enantioselectivity of heterocyclic-substituted aldehyde. This method is applied to the total synthesis of amino acids MeBmt [19] successfully. It was found that metallic gold was becoming a complex with isocyanate ester during the reaction by IR analysis of transition state. But metallic silver may be complexing with one molecule or two molecules, which is a balance in the middle. To form the excessive state of the phosphorus ligand with the metal complex or isocyanate was the key to high selectivity. Thus, they proposed a possible transition states (Figure 1-15).
Figure 1-15
Subsequently, it was reported the Aldol reaction of α-methyl-substituted ethyl isocyanate with aldehyde [20] by this type of catalyst, and the direct Aldol reaction of isocyanate phospholipids [21] and isocyanurate tosylate [22] with aldehyde. (Figure 1-16)
Figure 1-16
In addition to the metal gold that had been used in catalytic the Aldol Reaction of isocyanate , rhodium [23] has also been used in catalytic asymmetric Aldol Reaction of α-cyanate successfully to obtain 93% ee in the products. (Figure 1-17)
Figure 1-17
In the development of Aldol donor, in addition to the isocyanate and the diisocyanate, the Aldol product of the isothiocyanate (imide) also can obtain the amino acid derivatives through a simple derivation. Willis Group [24] first reported the preparation of Aldol reaction racemic with aldehyde and isothiocyanate in 2005. They use magnesium with triethylamine as a catalyst, with a pyridine as additives, which had a high overall yield on most substrate chemicals. The trade-off was the significant reduction in diastereoselectivity. In the experiments, they found that the type of metal and a counter ion had a great influence on the reaction yield. (Figure 1-18)
Figure 1-18
Subsequently, their group achieved the asymmetry at first [25]. In the elicitation of preparation of the racemic, they attempted to achieve a lone asymmetric product by the introduction of the chiral catalyst, using the complex of magnesium and oxazoline to catalyze the reaction. ( Figure 1-19)
Figure 1-19
The structure of the ethyl ester can’t obtain enantioselectivity in the screening of isothiocyanate ester. It is required to introduce Evans adjuvants and use isothiocyanato imide 81 to facilitate the reaction to achieve better results. (Figure 1-20)
Figure 1-20
Table 1.2 The enantioselective addition of imide 81 to aromatic aldehydes.
a General conditions: imide 81 (1 equiv), aldehyde (1.1 equiv), Mg(ClO4)2 (10 mol%), 83 (11 mol%), i-Pr2EtN (20 mol%), CH2Cl2, -78 oC. b Isolated yields of combined diastereomers. c Measured by 1H-NMR spectroscopy. d ee value of major diastereomer, measured by chiral HPLC using Chiracel OD column.
It can be seen from the table that the catalytic reaction system is a bit complex. The reaction conditions demand -78 oC to get high selectivity. There is a limitation of the universality of the substrate, which only fit aliphatic substrates that the enantioselectivity proportion of trans: cis is 1:1 for the ortho position.
The Seidel group [26] catalyzed asymmetric isothiocyanato imide with aldehydes Aldol Reaction using small molecule of thiourea in 2008. Large number of aliphatic aldehydes can be catalyzed to non-enantioselective and enantioselective in a low amount of catalyst and a mild reaction condition. The non-enantioselective had a great breakthrough compared to the first cases reported which the results were moderate to good. The author showed the prospects for industrial applications by expanding the amount of the reaction substrate reaction. (Figure 1-21)
Figure 1-21
For Aldol Reaction of the isocyanurate or isothiocyanate (imide), the current development of the receptor is an aldehyde, and there is almost no report of ketone. There were mainly two parts of challenges: 1) the activity of simple acetophenone was lower compared with the aldehyde; 2) the simple ketone had a relatively large steric hindrance, and the donor could not easily attack the substrate. (Figure 1-22)
Figure 1-22
Recently, Shibasaki group [27] has achieved a direct Aldol reaction with acetophenone and isothiocyanates for the first time. They make use of the complex of Schiffer alkali and magnesium to catalyze the reaction (Figure 1-20). The universality of the substrate is very wide, both the non-enantioselective and enantioselective can obtain good results, and the isothiocyanato can still have a good yield without adjuvants. This method was applied to the synthesis of optically active β-hydroxy-α-amino (Figure 1-23).
Figure 1-23
1.5 Conclusion
From the above literature, we found that the development of Aldol Reaction was step by step from first discovered Lewis acid which can promote the reaction to the development of a series to the central metal as a Lewis acid. Since the List and Barbas found to use proline to catalyze Aldol reaction, proline derivative, proline analogues catalyst and series of small organic molecules of diamines have been applied to the reaction successfully. The reaction conditions are more and more moderate. It was required a strict anhydrous anaerobic operation and -78 oC reactions to obtain a high enantioselectivity at first. Now many Aldol reactions were being in the aqueous phase directly and energy saving green. From the perspective of the development of the donor, it developed some value functional groups gradually. It need to pre-prepared silyl enol ether to a series of simple ketone ketone ester functional groups at first. The recently reported said the reactions with isocyanate or isothiocyanate ester (imide) can get many of the β-hydroxy-α-amino acid precursors.
The β-hydroxy-α-amino acid units have many important biologically active molecule skeletons. Aryl-substituted β-hydroxy-α-amino acid units are the main structural units of the many drug molecules. The natural product, such as vancomycin, ristocetin, diphenol amphotericin A having biological activity, and anti-inflammatory ring Marin et al. contains such structural unit. Currently, there are many ways to synthesize this structural unit. However, the Aldol reaction isothiocyanate ester (imide) with an aldehyde or ketone is the most direct and effective method for the synthesis of this molecule. It is possible to build the C-C bond step and generates two perspective chiral centers by this method.
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